The invention relates to nucleic acids encoding transcriptional regulatory sequences of a high-affinity melatonin receptor gene.
The high-affinity melatonin receptor is a membrane protein that is coupled to guanine nucleotide binding proteins (G proteins). G proteins, in turn, communicate ligand-activated receptor signals to the appropriate intracellular effector system(s). The hormone, melatonin, inhibits adenylyl cyclase causing a decrease in intracellular cyclic AMP (cAMP) concentration.
Melatonin, the principal hormone of the vertebrate pineal gland, elicits potent neurobiological effects. Melatonin influences circadian rhythm and mediates the effects of photoperiod on reproductive function in seasonally breeding mammals. In humans, melatonin administration has been shown to alleviate the symptoms of jet lag after air travel across several time zones. The hormone also has potent sedative effects in humans and may be a useful hypnotic agent.
Melatonin exerts its photoperiodic and circadian effects through pharmacologically specific, high-affinity receptors (Dubocovich, M. L. and Takahashi, J., Proc. Natl. Acad Sci. USA (1987) 84:3916-3920; Vanecek, J., J. Neurochem. (1988) 51:1436-1440; Reppert et al., Science (1988) 242:78-81). In seasonally breeding mammals, pineal melatonin secretion regulates seasonal responses to changes in day length (Bartness, T. J. and Goldman, B. D., Experientia (1989) 45:939-945; Karsch et al., Recent Prog. Horm. Res. (1984) 40:185-232). The only site containing melatonin 1a receptors in all photoperiodic species examined to date (Weaver, et al., Suprachiasmatic nucleus: the mind's clock. Klein, D. C., Moore, R. Y, and Reppert, S. M., eds. New York: Oxford University Press; (1991) pp. 289-308) is the pars tuberalis (PT), a portion of the pituitary gland. In contrast to other species, in humans melatonin 1a receptors are not consistently present in the PT.
High-affinity melatonin 1a (Mel.sub.1a) receptors are located in discrete regions of the vertebrate central nervous system of several mammalian species, including humans. Binding studies using the ligand 2-.sup.125 I!-iodomelatonin (.sup.125 I-melatonin or .sup.125 I!MEL) have identified high-affinity melatonin 1a receptors (K.sub.d &lt;2.times.10.sup.-10 M) in sites such as the suprachiasmatic nuclei (SCN), the site of a biological clock that regulates numerous circadian rhythms (Reppert et al., Science (1988) 242:78-81). To date, high-affinity melatonin receptors have not been identified in central nervous system tissues other than brain.
Receptor affinity is sensitive to guanine nucleotides and activation of the receptors consistently leads to the inhibition of adenylyl cyclase through a pertussis toxin-sensitive mechanism (Rivkees, S. A. et al., Proc. Natl. Acad. Sci. USA (1989) 86:3882-3886; Carlson, L. L. et al., Endocrinology (1989) 125:2670-2676; Morgan, P. J. et al., Neuroendocrinology (1989) 50:359-362; Morgan, P. J. et al., J. Neuroendocrinol. (1990) 2:773-776; Laitinen, J. T. and Saavedra, J. M., Endocrinology (1990) 126:2110-2115). High-affinity melatonin receptors thus appear to belong to the superfamily of G protein-coupled receptors.